Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia. Nonalcoholic fatty liver disease (NAFLD), one of the most common liver diseases worldwide 1 , is strongly associated with insulin resistance and features of metabolic syndrome such as obesity, hyperlipidemia, and type 2 diabetes 1,2. NAFLD ranges from simple steatosis to more advanced nonalcoholic steatohepatitis (NASH) characterized by steatosis in combination with inflammation and fibrosis 3,4. Besides insulin resistance, increased inflammatory cytokines, reactive oxygen species (ROS), and subsequent lipid peroxidation are thought to drive the progression of NASH, leading to liver cirrhosis and hepatocellular carcinoma 3,5. Thus, in addition to conventional approaches based on of diet-and exercise-related adjunct therapies, an effective therapeutic approach is urgently needed for NASH. Besides metabolic syndrome-related conditions, hyperuricemia, characterized by high serum uric acid (UA) levels, has also been linked to NAFLD. Several epidemiological studies have demonstrated that patients with NAFLD have significantly higher serum UA levels relative to controls, and elevated serum UA levels are an independent risk factor for NAFLD 6-8. Notably, UA itself has been reported to promote de novo lipogenesis and induce insulin resistance, both in vivo and in vitro, through increased NADPH oxidase (NOX)-mediated ROS

The authors investigated the DNA methylation patterns of the E-cadherin, Connexin 26 (Cx26), Rassf1a and c-fos genes in the early phase of rat hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined (CDAA) diet. Six-week-old F344 male rats were continuously fed with the CDAA diet, and three animals were then killed at each of 4 and 8 days and 3 weeks. Genomic DNA was extracted from livers for assessment of methylation status in the 5′ ′ ′ ′ upstream regions of E-cadherin, Cx26, Rassf1a and c-fos genes by bisulfite sequencing, compared with normal livers. The livers of rats fed the CDAA diet for 4 and 8 days and 3 weeks were methylated in E-cadherin, Cx26 and Rassf1a genes, while normal livers were all unmethylated. In contrast, normal livers were highly methylated in c-fos gene. Although the livers at 4 days were weakly methylated, those at 8 days and 3 weeks were markedly unmethylated. Methylation patterns of CpG sites in E-cadherin, Cx26 and Rassf1a were sparse and the methylation was not associated with gene repression. These results indicate that gene-specific DNA methylation patterns were found in livers of rats after short-term feeding of the CDAA diet, suggesting gene-specific hypermethylation might be involved in the early phase of rat hepatocarcinogenesis induced by the CDAA diet. (Cancer Sci 2007; 98: 1318-1322) I t is well known that unequivocal liver tumors can be induced by prolonged feeding of rats with a CD diet.(1-3) The choline deficiency causes fatty liver, cirrhosis and HCC in rats.(1-3) Possible mechanisms underlying liver carcinogenesis from the CD diet have been proposed to include the following: liver necrosis associated with subsequent regeneration; (4,5) induction of oxidative DNA damage and lipid peroxidation; (6)(7)(8)(9) and generation of genetic alterations.(10,11) It has also been considered that DNA hypomethylation might play an important role in liver carcinogenesis induced by methyl donor deficiency.(12,13) So far, hypomethylation of the c-fos, c-myc, and c-Ha-ras genes has been detected in the livers of rats fed with the CD diet. (14,15) The CDAA diet used in the present study is semi-synthetic, and provides stronger carcinogenic effects than the CD diet in rats. (16,17) The authors have previously reported the hypomethylation of c-myc in HCC resulting from the CDAA diet in rats. (18) In another study, hypermethylation of the E-cadherin and Cx26 genes was also detected in those tumors.(19) While genomewide hypomethylation occurs in several human cancer cells, sitespecific hypermethylation such as CpG islands of tumor suppressor genes, is also found.(20) It has been suggested that aberrant DNA methylation of promoter regions of genes is the major mechanism of gene silencing in the development of tumors. (21,22) In fact, aberrant DNA methylation has been found in a variety of human cancers, including liver tumors. (23)(24)(25)(26) However, it is unclear why DNA hypermethylation occurs in rat HCC induced by the CDAA diet despite methyl donor deficiency. Therefore, ...

No abstract

No abstract

We prepared 16 novel chiral peptide-pyrene organic luminophores with different distances between the fluorescent pyrene groups and investigated their properties in CHCl 3 at room temperature. The peptide-pyrene organic luminophores bearing two pyrene groups emit strong excimer circularly polarized luminescence (CPL) in the solution state. Two pendant pyrenyl groups in a series of chiral oligopeptides clearly revealed excimer CPL in chloroform at 480-490 nm (j g em j % (2-8) 3 10 -3 ). When the distance between the two pyrenes increased, the sign of the CPL signals was inverted twice, while the sign of the corresponding circular dichroism (CD) signals was retained, (j g CD j % (3-8) 3 10 -5 ).Recently, chiral organic and organometallic luminophores that efficiently emit circularly polarized luminescence (CPL) in the near-ultraviolet, visible, and near-infrared regions have received much attention because of their potential optoelectronic and photonic applications. [1][2][3][4] However, several studies of chiral luminophores having conformational freedom have suggested that controlling photoexcited chirality is one of the most challenging, difficult issues in chiral photochemistry because the sign and absolute magnitude of the CPL signals in the photoexcited state often differ from those of the circular dichroism (CD) signals in the ground state. [3] Possibly, the limited knowledge and understanding of photoexcited-state chirality may lead to unpredictable CPL and CD characteristics, because most textbooks of stereochemistry mainly discuss the chirality of ground-and thermally excited-states. Steady-state CPL spectroscopy detects photoexcited, short-lived chiral species, whereas steady-state CD spectroscopy focuses on long-lived chiral species at ambient temperature.According to a modified Jablonski diagram of chiral luminophores, short-lived chiral species (S 1 , S 2 , …) upon photoexcitation are first generated according to the Franck-Condon scheme at~10 -15 sec, and undergo non-radiative relaxation associated with ro-vibrational modes to the lowest vibronic state (S 1 state with n = 0), at~10 -11 -10 -12 sec. These species relax to the chiral ground state with CPL radiation at~10 -9 -10 -6 sec. [3] To ensure identical chirality between the photoexcited and ground states, enantiopairs of rigid scaffolds bearing achiral luminophores can be designed when a pair of (+)-and (-)-sign CPL luminophores is needed.Several novel strategies that enable the inversion of the CPL signs of luminophores without significant changes in the chiral scaffolds have been reported. [4] These works showed that the CPL signs of chiral luminescent systems are not determined by the stereogenic centers and/or stereogenic bonds of the substances. The inversion characteristics of the CPL sign can be modified by the choice of solvent, [4a, k] host matrix, [4e] stir direction at the sol-gel transition temperature, [4b] geometrical modifications of luminophores, [4c, d, g] heating-and-cooling treatments, [4f, k] and aggregation-and-disag...